NF-κB and STAT3 signaling uniquely stratifies survival in female glioblastoma patients

Sex differences in glioblastoma (GBM) incidence, prognosis, and response to treatment are well established. However, the molecular mechanisms that drive these differences are less well understood. In a pan-cancer study, we previously reported that female patients exhibit a sex bias towards upregulated inflammatory signaling across many cancers. Additionally, upregulated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling in GBM is associated with poor survival. Here, we report that only female GBM patients with higher expression of NF-κB- or IL6/JAK/STAT3-related genes have poorer survival compared to females with lower expression, a pattern not seen in male patients. Interestingly this sex difference was only evident in GBM tumors with wild-type epidermal growth factor receptor (EGFR). Using a mouse GBM model, we report that female GBM cells have similar stronger signatures in NF-κB and STAT3 signaling and exhibit a more robust response to manipulation of both pathways. Furthermore, female cells exhibited a stronger relationship between STAT3 activity and its sensitivity towards STAT3 inhibition. These results demonstrate that targeting NF-κB and STAT3 signaling in a sex-informed manner in GBM patients with wild-type EGFR tumors may improve patient response to treatment. Overall, this study highlights the mechanistic and clinical importance of analyzing data that is disaggregated by sex.